EP0132142A1 - Herstellung von kugelförmigen Gelatinegelen - Google Patents

Herstellung von kugelförmigen Gelatinegelen Download PDF

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Publication number
EP0132142A1
EP0132142A1 EP84304814A EP84304814A EP0132142A1 EP 0132142 A1 EP0132142 A1 EP 0132142A1 EP 84304814 A EP84304814 A EP 84304814A EP 84304814 A EP84304814 A EP 84304814A EP 0132142 A1 EP0132142 A1 EP 0132142A1
Authority
EP
European Patent Office
Prior art keywords
water
gelatin
process according
weight
aqueous solution
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP84304814A
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English (en)
French (fr)
Other versions
EP0132142B1 (de
Inventor
Osamu Hirai
Yoshiyuki Mukoyama
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Resonac Corp
Original Assignee
Hitachi Chemical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hitachi Chemical Co Ltd filed Critical Hitachi Chemical Co Ltd
Publication of EP0132142A1 publication Critical patent/EP0132142A1/de
Application granted granted Critical
Publication of EP0132142B1 publication Critical patent/EP0132142B1/de
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/09—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in organic liquids
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09H—PREPARATION OF GLUE OR GELATINE
    • C09H7/00—Preparation of water-insoluble gelatine
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09H—PREPARATION OF GLUE OR GELATINE
    • C09H9/00—Drying of glue or gelatine
    • C09H9/04—Drying of glue or gelatine in the form of granules, e.g. beads
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2389/00—Characterised by the use of proteins; Derivatives thereof
    • C08J2389/04—Products derived from waste materials, e.g. horn, hoof or hair
    • C08J2389/06—Products derived from waste materials, e.g. horn, hoof or hair derived from leather or skin

Definitions

  • This invention relates to a process for producing gelatin spherical gels, and more particularly to a process for producing polypeptide spherical gels suitable for an embolic agent or a carrier for impregnating pharmaceuticals.
  • embolic agents can be divided into two groups depending on purposes, that is, those having ephemeral embolism or having solubility and those having permanent embolism or having insolubility.
  • embolic agents for such purposes there are used those obtained by dissolving gelatin in water, foaming, subjecting to lyophilization to.form spongy body and cutting into several millimeters at a side or powdered; those obtained by adding formaldehyde to gelatin, conducting polymerization with heating, blowing air bubbles thereinto to form spongy body and cutting into several millimeters at a side or powdered; or the like.
  • these substances are impreganted with pharmaceuticals before use. But since these substances are in broken form, they have a defect in that they are difficult to adhere to blood vessels compared with spherical ones.
  • spherical substances available commercially there are known those made from organic polymers such as polystyrenes, poly(acrylic acid ester)s, polyvinyl alcohols, those made from inorganic substances such as silica, glass, etc. But these substances have a problem from the viewpoint of safety when they are included in a living body.
  • This invention provides a process for producing gelatin spherical gels which comprises dispersing an aqueous solution of gelatin in a dispersing medium obtained by dissolving water-insoluble ethyl cellulose in a non-polar organic solvent which is not miscible with water, and removing the water by distillation.
  • Gelatin has various molecular weights depending on raw materials used. In this invention, there is no particular limit to the molecular weight.
  • the concentration of gelatin in an aqueous solution of gelatin is preferably 5% by weight or more and the saturated concentration or lower. When the gelatin concentration is too low, the productivity is lowered.
  • an aqueous solution of gelatin and one or more crosslinking agents may be dispersed and subjected to a crosslinking reaction.
  • This can be conducted by adding the aqueous solution of gelatin and crosslinking agent dissolved in water to a liquid which is immiscible with water and stirring the resulting mixture.
  • the gelatin easily reacts with the crosslinking agent, it is preferable to disperse an aqueous solution of gelatin in the liquid immiscible with water, followed by addition of the crosslinking agent or an aqueous solution thereof thereto.
  • Gelatin has functional groups such as -NH 2 , -OH and -COOH which become reactive sites at the crosslinking reaction.
  • the crosslinking agent there can be used a water-soluble compound which can conduct a crosslinking reaction with gelatin.
  • the crosslinking agent having reactivity with the functional groups (e.g. -NH 2 group, -COOH.group) of gelatin are aliphatic dials such as glyoxal, propanedial, butanedial, pentanedial (glutaraldehyde), hexanedial, etc.; water-soluble polyvalent epoxides such as ethylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, glycerol polyglycidyl ether, diglycerol polyglycidyl ether, sorbitol polyglycidyl ether, diglycidyl methylhydantion, etc.
  • the amount of crosslinking agent is less than 5/100 equivalent weight per equivalent weight of reactive functional groups of gelatin (such as -NH 2 , -COOH), the crosslinking becomes insufficient to maintain the gelatin particles in spherical form. Even in such a case, when the water is removed by distillation according to this invention, the resulting gelatin particles can remain in the spherical form. If the water is not removed by distillation, the resulting particles are easily paste-likely agglomerated after the separation and washing of the particles with water.
  • the crosslinking agent it is preferable to use those which do not react with ethyl cellulose.
  • the dispersing medium usable in this invention is a compound which is not miscible with water, can dissolve the water-insoluble ethyl cellulose, and can form an azeotropic mixture with water or has a higher boiling point than water.
  • a compound is a non-polar organic solvent such as an alicyclic hydrocarbon, and the like.
  • the non-polar organic solvent can be used together with one or more polar solvents such as esters, ketones, halogenated alkanes, ethers, alcohols or aromatic hydrocarbons, these being unreactive with the crosslinking agent.
  • alicyclic hydrocarbons are those having 5 to 10 carbon atoms or alkyl substituted alcyclic hydrocarbons such as cyclopentane, cyclohexane, cycloheptane, methylcyclohexane, cyclooctane, decalin, etc. These alicyclic hydrocarbons can be used alone or as a mixture thereof.
  • the aromatic hydrocarbons include aromatic hydrocarbons and halogen substituted aromatic hydrocarbons having 6 to 8 carbon atoms. Examples of these aromatic hydrocarbons are benzene, toluene, xylenes, ethylbenzene, chlorobenzene, dichlorobenzene, bromobenzene, dibromobenzene, etc. These aromatic hydrocarbons can be used alone or as a mixture thereof.
  • esters there can preferably be used those obtained from fatty acids with 1 to 8 carbon atoms or aromatic carboxylic acids with 7 to 8 carbon atoms and alcanols having 1 to 8 carbons, alone or as a mixture thereof.
  • the esters are methyl acetate, ethyl acetate, n-butyl acetate, benzyl acetate, methoxyethyl acetate, methyl caproate, methyl benzoate, diethyl phthalate, etc.
  • ketones there can preferably be used aliphatic ketones having 5 to 8 carbon atoms, and aromatic ketones having 8 to 13 carbon atoms, alone or as a mixture thereof.
  • the ketones are methyl isobutyl ketone, cyclohexanone, methyl amyl ketone, hexyl methyl ketone, acetophenone, benzophenone, etc.
  • halogenated alkanes there can preferably be used alkanes having 1 to 4 substituted halogens alone or as a mixture thereof.
  • examples of the halogenated alkanes are methylene chloride, carbon tetrachloride, 1,2-dichloroethane, 1,1,2-trichloroethane, pentachloroethane, 1,2-dichloropropane, 1,2-dichlorbutane, 1,2-dibromoethane, etc.
  • ethers there can preferably be used straight-chain or cyclic ethers having 4 to 8 carbon atoms alone or as a mixture thereof.
  • the ethers are di-n-propyl ether, di-n-butyl ether, tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, etc.
  • alkanols having 4 to 8 carbon atoms there can preferably be used alkanols having 4 to 8 carbon atoms or alkoxy alkanols having 4 to 8 carbon atoms alone or as a mixture thereof.
  • examples of the alcohols are n-butanol, n-octanol, methoxyethanol, ethoxyethanol, butoxyethanol, diethylene glycol monomethyl ether, etc.
  • the water-insoluble ethyl cellulose there can be used those having an ethoxy group content of 43 to 50%.
  • the words "ethoxy group content” mean a weight percent of the ethoxy group in ethyl cellulose.
  • those having relatively smaller ethoxy group content for example, those having 43 to 46% by weight of the ethoxy group content, are hardly soluble in the above-mentioned non-polar organic solvent. Therefore, when the above-mentioned non-polar organic solvent is used alone as the dispersing medium, it is preferable to use those having 47 to 50% by weight of the ethoxy group content.
  • the water-insoluble ethyl cellulose When the water-insoluble ethyl cellulose is used in combination with one or more above-mentioned non-polar organic solvents such as alicyclic hydrocarbons, there can be formed a particularly preferable dispersing medium. But since the solubility of ethyl cellulose in a non-polar organic solvent is poor as mentioned above, it is preferable to use the above-mentioned polar solvent or aromatic hydrocarbon together as dispersing medium.
  • the aromatic hydrocarbon can be used in an amount of preferably 400% by weight or less, more preferably 200% by weight or less based on the weight of the non-polar organic solvent.
  • the latter component can be used in an amount of preferably 200% by weight or less, more preferably 150% by weight or less, based on the weight of the non-polar organic solvent.
  • the latter component can be used in an amount of preferably 30% by weight or less, more preferably 20% by weight or less, based on the weight of the non-polar organic solvent.
  • the water-insoluble ethyl cellulose can be used in an amount of preferably 0.05 to 10% by weight, more preferably 0.5 to 5% by weight, based on the total weight of the dispersing medium.
  • the dispersing medium used in this invention obtained by dissolving the water-insoluble ethyl cellulose in the water-immiscible organic dispersing medium can disperse non-crosslinked gelatin effectively.
  • the dispersing medium in an amount of preferably 50 to 2000% by weight, more preferably 100 to 1000% by weight, based on the total weight of gelatin, the crosslinking agent and water (hereinafter referred to as "the amount of water phase").
  • the amount of water phase a phase of water phase
  • a method of mixing the two with stirring there can be employed a method of adding the aqueous solution of gelatin to the dispersing medium with stirring, and the like.
  • a stirring method there can be employed a stirring method by using an emulsator accompanying high-speed shearing, a stirring method by using a marine propeller stirrer or magnetic stirrer not accompanying mechanical cutting or grinding, and the like. These stirring methods can be selected depending on the desired particle size.
  • the dispersion of the aqueous solution of gelatin it is preferable to conduct the dispersion of the aqueous solution of gelatin at a temperature from room temperature to the boiling point of water or the dispersing medium. After the completion of dispersion, the water is removed by distillation at elevated temperatures or under reduced pressure.
  • the resulting gelatin spherical particles can be recovered by filtration or decantation.
  • the solvent which forms an azeotropic mixture with water can be removed by distillation together with the distillation of water. In such a case, when the amount of dispersing medium becomes too small, such a solvent can be supplemented during the distillation.
  • the washing of the resulting particles is conducted by using a solvent having a relatively low boiling point and the drying is conducted under atmospheric or reduced pressure, the particles can be purified while maintaining the spherical form.
  • a dispersing medium comprising 150 g of decalin and 50g of toluene, 6 g of ethyl cellulose (the ethoxy group content: 49% by weight) was dissolved.
  • the resulting dispersing medium was introduced into a 500-ml flask equipped with a cooling tube and agitating blades made from polytetrafluoroethylene.
  • the stirring speed was controlled at 400 r.p.m. and the temperature was raised to 70°C.
  • 40 g of a 30% by weight aqueous solution of gelatin dissolved at 50°C was added to the flask, wherein the stirring was continued for 5 minutes to produce spherical particles.
  • the temperature was raised to 110°C to remove the water by distillation.
  • the resulting particles were collected by filtration, washed with ethyl acetate, followed by washing with acetone.
  • the particles had a spherical form and a particle size of 0.1 to 1 mm when observed by
  • a dispersing medium of 200 g of decalin 6 g of ethyl cellulose (the ethoxy group content: 49% by weight) was dissolved.
  • the resulting dispersing medium was introduced into a 500-ml flask equipped with a cooling tube and agitating blades made from polytetrafluoroethylene.
  • the stirring speed was controlled at 400 r.p.m. and the temperature was raised to 70°C.
  • 40 g of a 30% by weight aqueous solution of gelatin dissolved at 50°C was added to the flask, wherein the stirring was continued for 5 minutes to produce spherical particles.
  • the temperature was raised to 110°C to remove the water by distillation.
  • the resulting particles were collected by filtration, washed with ethyl acetate, followed by washing with acetone.
  • the particles had a spherical form and had a particle size of 0.1 to 1 mm when observed by a microscope.
  • a dispersing medium comprising 150 g of decalin and 50 g of toluene, 6 g of ethyl cellulose (the ethoxy group content: 49% by weight) was dissolved.
  • the resulting dispersing medium was introduced into a 500-ml flask equipped with a cooling tube and agitating blades made from polytetrafluoroethylene. The stirring speed was controlled at 400 r.p.m. and the temperature was raised to 70°C.
  • a dispersing medium comprising 150 g of decalin and 50 g of toluene, 6 g of ethyl cellulose (the ethoxy group content: 49% by weight) was dissolved.
  • the resulting dispersing medium was introduced into a 500-ml flask equipped with a cooling tube and agitating blades made from polytetrafluoroethylene. The stirring speed was controlled at 400 r.p.m. and the temperature was raised to 70°C. Then, 40 g of a 30% by weight aqueous solution of gelatin dissolved at 50°C was added to the flask, wherein the stirring was continued for 5 minutes to produce spherical particles. Then, the particles were collected by filtration without removal of the water by distillation, washed with ethyl acetate, followed by washing with acetone. The resulting particles were agglomerated to form a paste-like solid.
  • this invention can provide safe gelatin spherical particles.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Processes Of Treating Macromolecular Substances (AREA)
  • Medicinal Preparation (AREA)
  • Materials For Medical Uses (AREA)
EP19840304814 1983-07-14 1984-07-13 Herstellung von kugelförmigen Gelatinegelen Expired EP0132142B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP128463/83 1983-07-14
JP58128463A JPS6021764A (ja) 1983-07-14 1983-07-14 ゼラチン球状粒子の製造法

Publications (2)

Publication Number Publication Date
EP0132142A1 true EP0132142A1 (de) 1985-01-23
EP0132142B1 EP0132142B1 (de) 1987-07-08

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EP19840304814 Expired EP0132142B1 (de) 1983-07-14 1984-07-13 Herstellung von kugelförmigen Gelatinegelen

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EP (1) EP0132142B1 (de)
JP (1) JPS6021764A (de)
DE (1) DE3464631D1 (de)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999030741A3 (de) * 1997-12-12 1999-08-19 Max Delbrueck Centrum Mittel zur gentherapie von tumorerkrankungen, neurodegenerativen, herzkreislauf- und autoimmunerkrankungen
CN110218338A (zh) * 2019-05-21 2019-09-10 江汉大学 一种导电明胶弹性体的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE813188C (de) * 1950-06-25 1951-09-10 Hellmuth Holz Dr Verfahren zur Herstellung von Leimpulver
DE1445105A1 (de) * 1959-10-01 1969-01-09 Merck & Co Inc Verfahren zur Herstellung eines pharmazeutischen Traegers
FR2271270A1 (en) * 1974-05-17 1975-12-12 Kodak Pathe Stable hardened gelatine granules prepn. - allowing incorporation of photographic reactants in concentric coated layers

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE813188C (de) * 1950-06-25 1951-09-10 Hellmuth Holz Dr Verfahren zur Herstellung von Leimpulver
DE1445105A1 (de) * 1959-10-01 1969-01-09 Merck & Co Inc Verfahren zur Herstellung eines pharmazeutischen Traegers
FR2271270A1 (en) * 1974-05-17 1975-12-12 Kodak Pathe Stable hardened gelatine granules prepn. - allowing incorporation of photographic reactants in concentric coated layers

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999030741A3 (de) * 1997-12-12 1999-08-19 Max Delbrueck Centrum Mittel zur gentherapie von tumorerkrankungen, neurodegenerativen, herzkreislauf- und autoimmunerkrankungen
CN110218338A (zh) * 2019-05-21 2019-09-10 江汉大学 一种导电明胶弹性体的制备方法

Also Published As

Publication number Publication date
DE3464631D1 (en) 1987-08-13
JPS6021764A (ja) 1985-02-04
EP0132142B1 (de) 1987-07-08

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